Abstract
BackgroundAlexander disease, an autosomal dominant leukodystrophy, is caused by missense mutations in GFAP. Although mostly diagnosed in children, associated with severe leukoencephalopathy, milder adult forms also exist.MethodsA family affected by adult-onset spastic paraplegia underwent neurological examination and cerebral MRI. Two patients were sequenced by whole exome sequencing (WES). A candidate variant was functionally tested in an astrocytoma cell line.ResultsThe novel variant in GFAP (Glial Fibrillary Acidic Protein) N-terminal head domain (p.Gly18Val) cosegregated in multiple relatives (LOD score: 2.7). All patients, even those with the mildest forms, showed characteristic signal changes or atrophy in the brainstem and spinal cord MRIs, and abnormal MRS. In vitro, this variant did not cause significant protein aggregation, in contrast to most Alexander disease mutations characterised so far. However, cell area analysis showed larger size, a feature previously described in patients and mouse models.ConclusionWe suggest that this variant causes variable expressivity and an attenuated phenotype of Alexander disease type II, probably associated with alternative pathogenic mechanisms, that is, astrocyte enlargement. GFAP analysis should be considered in adult-onset neurological presentations with pyramidal and bulbar symptoms, in particular when characteristic findings, such as the tadpole sign, are present in MRI. WES is a powerful tool to diagnose atypical cases.
Funder
Fundació la Marató de TV3
Centre for Biomedical Research on Rare Diseases
Hesperia Foundation
Ministerio de Economia, Industria y Competividad
Secretariat for Universities and Research of the Ministry of Business and Knowledge of the Government of Catalonia
Instituto de Salud Carlos III
Subject
Genetics(clinical),Genetics
Cited by
9 articles.
订阅此论文施引文献
订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献